Gene 33/Mig-6, a transcriptionally inducible adapter protein that binds GTP-Cdc42 and activates SAPK/JNK - A potential marker transcript for chronic pathologic conditions, such as diabetic nephropathy. Possible role in the response to persistent stress

Chronic stresses, including the mechanical strain caused by hypertension or excess pulmonary ventilation pressure, lead to important clinical conseque nces, including hypertrophy and acute respiratory distress syndrome. Pathol ogic hypertrophy contributes to decreased organ function and, ultimately, o rgan failure; and cardiac and diabetic renal hypertrophy are major causes o f morbidity and morality in the developed world. Likewise, acute respirator y distress syndrome is a serious potential side effect of mechanical pulmon ary ventilation. Whereas the deleterious effects of chronic stress are well established, the molecular mechanisms by which these stresses affect cell function are still poorly characterized. gene 33 (also called mitogen-induc ible gene-6, mig-6) is an immediate early gene that is transcriptionally in duced by a divergent array of extracellular stimuli. The physiologic functi on of Gene 33 is unknown. Here we show that gene 33 mRNA levels increase sh arply in response to a set of commonly occurring chronic stress stimuli: me chanical strain, vasoactive peptides, and diabetic nephropathy. Induction o f gene 33 requires the stress-activated protein kinases (SAPKs)/c-Jun NH2-t erminal kinases, This expression pattern suggests that gene 33 is a potenti al marker for diabetic nephropathy and other pathologic responses to persis tent sublethal stress. The structure of Gene 33 indicates an adapter protei n capable of binding monomeric GTPases of the Rho subfamily. Consistent wit h this, Gene 33 interacts in vivo and, in a GTP-dependent manner, in vitro with Cdc42Hs; and transient expression of Gene 33 results in the selective activation of the SAPKs, These results imply a reciprocal, positive feedbac k relationship between Gene 33 expression and SAPK activation. Expression o f Gene 33 at sufficient levels may enable a compensatory reprogramming of c ellular function in response to chronic stress, which may have pathophysiol ogical consequences.